The long-term objective of the study is to find means to improve the effectiveness of hyperthermia a an adjuvant to radiotherapy by exploiting the differences in physiological and biochemical factors in tumors and normal tissues. The strategy of current clinical hyperthermia is to selectively damage tumor blood vessels. We found that when tumor blood vessels are heated at moderate temperatures, vascular thermotolarance develops, which reduces the chance of destroying tumor vessels by subsequent heating. Our 1st specific aim is to investigate in detail the kinetics of vascular thermotolerance. Our recent studies indicate that tumor pO2 significantly increases upon heating at moderate temperatures particularly when the tumor blood vessels are thermotolerant. It appears that vascular thermotolerance may be undesirable for the destruction of blood vessels but it is desirable for improving tumor oxygenation and increasing the radioresponse of tumors. Our 2nd specific am is to determine the increase in pO2 in tumors by hyperthermia before and after induction of vascular thermotolerance. Increase in intracellular acidity increases cellular thermosensitivity. Tumor cells possess effective pHi regulatory mechanisms through which the intracellular acidity of cells in tumors is maintained near neutral despite the acidic intratumor environment. Our 3rd specific aim is to explore the possibility of lowering pHi by interfering with the pHi regulatory mechanisms thereby increasing the thermosensitivity of tumors. It has become increasingly clear that apoptosis is a major mode of hyperthermia-induced cell death. Our 4th specific aim is to delineate the role of pHi in hypethermia-induced apoptosis. The information obtained in the study on the changes i blood flow and pO2 in tumors may enable us to design new strategies to use hyperthermia for increasing the radioresponse of tumors. The study on the role of pHi in thermosensitization and heat-induced apoptosis may provide means to exploit the acidic intratumor environment for improving the efficacy of hyperthermia treatment of tumors.